Venezuelan equine encephalitis virus (VEEV), a member of the alphavirus genus of the family Togaviridae, is an important mosquito-borne pathogen in humans and equides [1]. VEEV infections mainly target the central nervous system and lymphoid tissues causing severe encephalitis in equines and a spectrum of human diseases ranging from unapparent or sub-clinical infection to acute encephalitis. Neurological disease appears in 4-14% of cases. The incidence of human infection during equine epizootics could be up to 30%. Mortality associated with the encephalitis in children is as high as 35%. Recent outbreaks in Venezuela and Colombia in 1995 resulted in around 100,000 human cases with more than 300 fatal encephalitis cases [2]. Furthermore, VEEV is highly infectious by aerosol inhalation in humans and other animals. However, there are no antiviral drugs available that are effective against VEEV although currently there are two forms of IND (investigational new drug) VEEV vaccines available for human and veterinary use: TC-83, a live-attenuated Trinidad donkey strain and C-84, a formalin-inactivated TC-83 [3,4]. However, for various reasons, these vaccines are far from satisfactory. For example, approximately 20% of recipients that receive the TC-83 vaccine fail to develop neutralizing Abs, while another 20% exhibit reactogenicity. In addition, the TC-83 vaccine could revert to wild-type form. The vaccine C-84 is well tolerated, but requires multiple immunizations, periodic boosts, and fails to provide protection against aerosol challenge in some rodent models.
Like the other alphaviruses, VEEV is an enveloped virus, consisting of three structural proteins: a capsid encapsidating the viral RNA genome, and two envelope glycoproteins, E1 and E2. E1 and E2 form heterodimers, which project from the virus envelope as trimer spikes. Epitopes on the spikes are the targets of neutralizing Abs. Studies have shown that the viral neutralizing epitopes are mainly located on the E2 protein, and that the E2C epitope appears to be the hub of the neutralization epitopes [5,6]. The murine monoclonal Ab (mAb) 1A4A1 [14] is specific for E2C. This mAb has been shown to be efficient in protecting animals from a lethal peripheral challenge with virulent VEEV [7].
Murine mAbs, however, have serious disadvantages as therapeutic agents in humans [8]. For example, one of the problems associated with using murine mAbs in humans is that they may induce an anti-mouse Ab response. Further, repeat administration of murine mAbs may result in rapid clearance of the murine mAbs and anaphylaxis, which can sometimes be fatal. To overcome this hurdle, the humanization of murine mAbs has been proposed, by which process murine Ab frameworks are replaced by human Ab ones in order to reduce immunogenicity of Abs in humans [9,10].
An effective means of immunization against VEEV is needed. In particular, a means of prophylaxis against VEEV and/or a therapy for VEEV infection is desired.